February 2018

GLAUCOMA

Pharmaceutical focusEye on compounded glaucoma drops

by Maxine Lipner EyeWorld Senior Contributing Writer

“When patients are on four drops, the probability of them coming back and not having run out of at least one of them is low. If they just have one drop to worry about, that’s more manageable.”
—Nathan Radcliffe, MD

Day 1 postoperative photograph of a patient who underwent cataract extraction with intravitreal placement of triamcinolone and moxifloxacin. While the patient is likely to notice some floaters, the patient will likely not require any topical therapy following surgery.
Source: Nathan Radcliffe, MD

Although these two medications have been generic for 5 years or longer, the patient using them was paying $115 monthly for co-pays.
Source: Nathan Radcliffe, MD

What practitioners are considering when it comes to these medications

Glaucoma drops today are not limited to brand name and generic medications that patients can pick up at their local pharmacy. Many are also turning to compounded glaucoma medications such as Simple Drops (Imprimis Pharmaceuticals, San Diego) and Omni (Ocular Science, Manhattan Beach, California) to circumvent a variety of issues, according to Nathan Radcliffe, MD, assistant professor of ophthalmology, New York Eye and Ear Infirmary, New York. EyeWorld took a closer look at compounded drops in the glaucoma arena.
Gary Novack, PhD, president, PharmaLogic Development, San Rafael, California, and visiting professor of pharmacology and ophthalmology, University of California Davis School of Medicine, Sacramento, pointed out that for centuries pharmacists have followed physicians’ orders on compounding personalized products on a patient by patient basis. “U.S. food and drug law allows physicians to customize therapy for individual patients, including off-label use of products as they deem therapeutic for the patient,” Dr. Novack said. “Compounding pharmacies have played a special role in this therapeutic process.” For example, oral cyclosporine was being compounded into a topical product in the 1900s before a commercial ophthalmic cyclosporine was approved by the FDA, Dr. Novack noted.

Considering compounded drops

Practitioners today are bringing such drops into their glaucoma practices. Dr. Radcliffe sees compounding medications as making sense for patients in many respects. He cited the ability to avoid mix-ups by combining several glaucoma drops into one bottle. “The main issue I have to combat is patient confusion,” he said, adding that it’s not uncommon for a patient to take the timolol cap, for example, and put it on the prednisolone bottle. This can cause them to take the wrong dose of the medication. “After surgery, you may ask, ‘Are you using the bottle with the pink cap four times a day?” Dr. Radcliffe said. While patients may swear they’re following directions, when they bring the bottles in for him to review, the mix-up becomes clear.
This tends to happen more with those who have a lower level of health literacy, he finds. With this in mind, Dr. Radcliffe uses compounded medications for both glaucoma and cataract care.
Even when there are no mix-ups, in terms of compliance, reducing the number of drops needed can be a boon for patients. “We know that patients have trouble with just two eye drop bottles,” Dr. Radcliffe said. He finds that compliance drops off, and instead of doing patients a favor by adding a medicine to the regimen, their glaucoma may end up being under worse control than ever, with gaps in therapy. “When patients are on four drops, the probability of them coming back and not having run out of at least one of them is low,” he said. “If they just have one drop to worry about, that’s more manageable.”
In addition, using just one compounded medication can potentially reduce exposure to preservatives, Dr. Radcliffe pointed out. Preservative exposure is much greater if patients are taking drops from four separate bottles instead of just one.
The market may also be ripe from a financial standpoint. Dr. Radcliffe said that the generics market has seen a steep increase in prices lately. “We have an entirely genericized market, which means that some of the leading formulations from each class of medications are available,” he said. “This should be a time of amazing savings for glaucoma patients, but some patients are paying as much for generic medicine as they would for brand name medication.” This is because the prices are often controlled at the pharmacy and not by the generic manufacturer, and many institutions and insurance formularies insist that practitioners prescribe these generic drugs.
“When you don’t have the choice, there’s the ability for generic manufacturing pharmaceutical companies to raise prices,” Dr. Radcliffe said. As a result, it’s not uncommon to have a glaucoma patient who is on three generic medications paying more than $100 in copays per month. For some patients in this situation, it may make sense to switch to a more affordable compounded medication. The question becomes, does a patient on four separate glaucoma medications typically have a copay that’s greater than $50 per month? “The answer is about half the time,” Dr. Radcliffe said. “So for half of those people, something like this could save them a little money and be easier.”
There are two compounding pharmacies that have put out a variety of formulations to try to address these issues. One of these companies, Ocular Science, has 503 A status and is a patient-specific compounding pharmacy. Such pharmacies tend to be smaller. “They have voluntary inspections by the FDA and aren’t tightly regulated,” Dr. Radcliffe said. They have combinations of latanoprost and timolol in one bottle and they have all four glaucoma agents—timolol, brimonidine, dorzolamide, and latanoprost —in one bottle.
Imprimis is a 503 B compounding pharmacy, which manufactures preservative-free glaucoma formulations. “With 503 B compounding pharmacies, because they’re mass producing, they do have some fairly frequent inspections,” Dr. Radcliffe said. “They have all of the combinations that you would want.”

Possible downsides

One potential downside is the uncertain status of some compounded medication. “It’s interesting because we’re in a gray zone legislatively,” Dr. Radcliffe said, adding that replicating large quantities of these eye drops in combination may have legal implications.
Dr. Novack pointed out that drugs that have been FDA approved and marketed meet good manufacturing practice standards for release and stability. “These criteria include the concentration of active (i.e., the named product molecule), as well as sterility, pH, and in the case of preserved products, the ability to kill microbes,” Dr. Novack said. “Most products compounded by pharmacies are not tested, so this quality cannot be assured.”
Preservative-free glaucoma formulations may bring additional concerns. “While the active molecules are approved in individual or in some cases fixed-dose combinations, the non-preserved formulation has not undergone the chemical, preclinical and clinical evaluation, or benefit/risk evaluation of FDA-approved products,” Dr. Novack said. What’s more, some double and triple fixed-dose combinations have been evaluated in controlled studies, albeit in different formulations, and in some cases were judged by the FDA not to have a favorable benefit/risk ratio.
There is also the question of infection with compounded medications. In Dr. Radcliffe’s view, with the compounded drops, such concerns are not founded. “It needs to be said that any infections related to compounded medications have had to do with injected medications,” he said. Topical medicines are much less likely to be associated with ocular infections. Other questions, like how well the bottles do if they’re not refrigerated or how well they stay preserved, is something that practitioners need to think about, Dr. Radcliffe said.
In addition to glaucoma medication, compounded therapy has found its way into cataract surgery. “This can include combinations of antibiotic, steroid, and nonsteroidal anti-inflammatory that are dosed four times a day after cataract surgery. This can be particularly confusing and burdensome for glaucoma patients who are taking other medications as well,” Dr. Radcliffe said. “If our patients are taking glaucoma drops and they have cataract surgery, they can end up on six drops, and that gets confusing,” he said. “You may find that other things, such as dropless cataract surgery, can help.”
Dr. Radcliffe has been using compounded Tri-Moxi (triamcinolone/moxifloxacin, Imprimis) for cataract surgery. “When I perform a cataract surgery with MIGS, at the end of the cataract I inject the Tri-Moxi and often have patients who are completely off all glaucoma and cataract drops after cataract surgery,” Dr. Radcliffe said, adding that it is a great thing for a patient to come in for surgery on three drops, have the surgery, and end up on no drops. He finds that the patients are very grateful to have dropless cataract surgery and see the burden of their glaucoma drops reduced at the same time.
Overall, Dr. Radcliffe views this as an exciting time, but acknowledges that the field is still very much evolving. “I think there are issues that still need to be resolved,” he said. “Some are financial, some have to do with safety and efficacy, and others have to do with practice dynamics.” Ultimately, it’s going to be a question of whether the majority of ophthalmologists embrace these therapies, he concluded.